RIBOZYME AND OMICS

PIPELINE

RZ-003

Alzheimer’s Disease (AD)

Medical unmet needs
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    High patient growth rate
    Annual increase in Alzheimer patients : 10 million
    The number of Alzheimer patients in the world will more than triple in 35 years. (74.7 million in 2030, 131.5 million in 2050)
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    Lack of effective therapies
    Effectiveness : Local and temporary improvement in cognitive function
    Lack of DMST (Disease Modifying / Slowing Therapy) with active therapeutic actions
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    Increased social costs
    Higher cost of illness than other diseases
    The cost of illness will also increase in proportion to the number of patients
    USD 604 bn. in 2010
    X 3
    USD 2 trillion in 2030
Growing trend of Alzheimer patients
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Current therapies and side effects
Therapies Efficacy / Side effects
Cholinerginc Drug(AchE inhibitor)

Improvement in cognitive function caused by increased Acetylcholine

Gastrointestinal disorders, nausea, abdominal pain, diarrhea, anorexia (20~30% patient group), bradycardia
Memantine(NMDA receptor antagonist)

Suppression of neuronal damage, restoration of neuronal cell’s physiological function

Dizziness, anxiety, delusion, hallucination
Development of innovative therapies with targeting new mechanism target / early stag target
APOE (Apolipoprotein E) – AD target molecule
34kDa, Role of lipid and cholesterol delivery
3 Alleles : E2, E3, E4 (Point mutation only 2 nucleotide)
E4 : highest AD risk factor (lowest lipidation)
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Amino acid APOE2 APOE3 APOE4
112aa Cys Cys Arg
158aa Cys Arg Arg
AD incidence according to APOE genetic trait
Genotype Population (%) Adb (%) #Population #AD Riskc (%) If all US
ε2/2 1 0.1 0.5M 0.004M 0.08 0.4M
ε2/3 12 4 5.5M 0.18M 3.2 1.5M
ε3/3 60 35 27.6M 1.4M 5.1 2.3M
ε3/4 21 42 9.6M 1.7M 18 8.2M
ε4/4 2 16 0.9M 0.6M 67 30.7M
RISKY INHERITANCE
People who carry the gene variant APOE4 tend to develop Alzheimer’s at a younger age than those with two copies of APOE3.
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*Nature 2014

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*CNS Drugs 2016

APOE4-related Alzheimer’s incidence
Decrease degradation/elimination of Aβamyloid plaque formation
Tau hyperphosphorylationformation of neurofibrillary tangles, intracellular microskeletal damage
APOE protein decreases intracellular stability, increases degradation.Neurotoxic protein fragments
Accelerate BBB breakdown (independent of Ab and Tau)

* Neuron 2008 / Mo Neurodegener 2015 / Nature 2017, 2020/ Nat Med 2018

APOE4
Involved in both amyloid beta and tau protein phenomena
APOE2
APOE-related amyloid plaques formation
Formation of neurofibrillary tangles by Tau hyperphosphorylation
Reduced neurotoxic APOE fragments
RNA replacement enzyme vector-based AD therapeutic agent targeting APOE4
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Advantages of technology
  • Multi-function

    Inhibition of APOE4 RNA expression & expression of therapeutic RNA

  • Multi-targeting

    Inhibition of Aß and Tau aggregation, neurotoxic protein fragmentation

  • Modular engineering

    Possible introduce multiple genes to improve the therapeutic effect in one construct

  • Early treatment available

    Early treatment can be started with APOE genetic testing